Liu Zhihua, Feng Yu, Zhao Hang, Hu Jinping, Chen Yanmin, Liu Dongdong, Wang Hongliang, Zhu Xiangyang, Yang Hongzhen, Shen Zhufang, Xia Xuejun, Ye Jun, Liu Yuling
Beijing Wehand-Bio Pharmaceutical Co, Ltd., Beijing, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Front Pharmacol. 2023 Feb 17;14:1136772. doi: 10.3389/fphar.2023.1136772. eCollection 2023.
Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from twigs of mulberry ( L., genus in the Moraceae family) was approved by the National Medical Products Administration in 2020 for the treatment of type 2 diabetes mellitus. In addition to excellent hypoglycemic effect, increasing evidence has confirmed that SZ-A exerts multiple pharmacological effects, such as protecting pancreatic -cell function, stimulating adiponectin expression, and alleviating hepatic steatosis. Importantly, a specific distribution of SZ-A in target tissues following oral absorption into the blood is essential for the induction of multiple pharmacological effects. However, there is a lack of studies thoroughly exploring the pharmacokinetic profiles and tissue distribution of SZ-A following oral absorption into the blood, particularly dose-linear pharmacokinetics and target tissue distribution associated with glycolipid metabolic diseases. In the present study, we systematically investigated the pharmacokinetics and tissue distribution of SZ-A and its metabolites in human and rat liver microsomes, and rat plasma, as well as its effects on the activity of hepatic cytochrome P450 enzymes (CYP450s). The results revealed that SZ-A was rapidly absorbed into the blood, exhibited linear pharmacokinetic characteristics in the dose range of 25-200 mg/kg, and was broadly distributed in glycolipid metabolism-related tissues. The highest SZ-A concentrations were observed in the kidney, liver, and aortic vessels, followed by the brown and subcutaneous adipose tissues, and the heart, spleen, lung, muscle, pancreas, and brain. Except for the trace oxidation products produced by fagomine, other phase I or phase II metabolites were not detected. SZ-A had no inhibitory or activating effects on major CYP450s. Conclusively, SZ-A is rapidly and widely distributed in target tissues, with good metabolic stability and a low risk of triggering drug-drug interactions. This study provides a framework for deciphering the material basis of the multiple pharmacological functions of SZ-A, its rational clinical use, and the expansion of its indications.
桑枝生物碱（桑植）（SZ-A）源自桑科桑属植物（L.）的嫩枝，于2020年获得国家药品监督管理局批准用于治疗2型糖尿病。除了出色的降血糖作用外，越来越多的证据证实SZ-A还具有多种药理作用，如保护胰岛β细胞功能、刺激脂联素表达以及减轻肝脂肪变性。重要的是，SZ-A口服吸收进入血液后在靶组织中的特定分布对于诱导多种药理作用至关重要。然而，目前缺乏对SZ-A口服吸收进入血液后的药代动力学特征和组织分布进行全面研究，尤其是与糖脂代谢疾病相关的剂量线性药代动力学和靶组织分布。在本研究中，我们系统地研究了SZ-A及其代谢产物在人和大鼠肝微粒体、大鼠血浆中的药代动力学和组织分布，以及其对肝细胞色素P450酶（CYP450s）活性的影响。结果显示，SZ-A迅速吸收入血，在25-200mg/kg剂量范围内呈现线性药代动力学特征，并广泛分布于糖脂代谢相关组织中。在肾脏、肝脏和主动脉血管中观察到SZ-A的浓度最高，其次是棕色和皮下脂肪组织，以及心脏、脾脏、肺、肌肉、胰腺和大脑。除了法戈明产生的微量氧化产物外，未检测到其他I相或II相代谢产物。SZ-A对主要的CYP450s没有抑制或激活作用。总之，SZ-A在靶组织中迅速且广泛分布，具有良好的代谢稳定性和较低的引发药物相互作用的风险。本研究为阐明SZ-A多种药理功能的物质基础、其合理的临床应用以及适应证的拓展提供了框架。
